PATIENTS undergoing AML transplant with a CRISPR edited donor graft achieved rapid engraftment and tolerated subsequent targeted maintenance therapy without prolonged haematologic toxicity, according to findings from a multicentre phase 1/2a study in high-risk acute myeloid leukaemia and myelodysplastic syndrome.
Patients with acute myeloid leukaemia and myelodysplastic syndrome remain at substantial risk of relapse following allogenic haematopoietic cell transplantation. Post transplant maintenance strategies may reduce relapse risk, although toxicity affecting donor derived cells has limited broader use of targeted agents. Investigators evaluated tremtelectogene empogeditemcel, a CRISPR–Cas9 gene edited allogeneic transplant product lacking CD33, designed to protect donor graft cells from the effects of subsequent CD33 targeted therapy with gemtuzumab ozogamicin.
The open label study enrolled adult patients with acute myeloid leukaemia or myelodysplastic syndrome who were considered at high risk of relapse. Participants received tremtelectogene empogeditemcel after myeloablative conditioning, followed by gemtuzumab ozogamicin maintenance administered every 28 days at doses ranging from 0.5–2.0 mg m−2.
Rapid Engraftment After AML Transplant
All 30 patients receiving the gene edited graft met the primary endpoint of neutrophil engraftment by Day 28. Median time to neutrophil engraftment was 10 days (95% CI: 9–10). Secondary assessments included graft versus host disease, graft failure, transplant related mortality, survival outcomes, and the proportion of CD33 negative myeloid cells.
Nineteen patients subsequently received gemtuzumab ozogamicin maintenance therapy during either phase 1 dose escalation or phase 2 dose expansion. The trial was stopped early, although the completed phase 1 component was included in the final analysis.
Investigators reported that gemtuzumab ozogamicin was safely tolerated up to the recommended phase 2 dose of 2 mg m−2. Importantly, no prolonged high-grade cytopenias were observed following maintenance treatment, supporting the feasibility of combining targeted therapy with the edited donor graft approach.
Safety Findings Support Further Investigation
The most frequently reported adverse events were cytopenias and infections. Three cases of transplant related mortality occurred and were attributed to renal failure, sepsis, and sinusoidal obstruction syndrome.
Researchers concluded that the AML transplant approach demonstrated safe, rapid, and robust engraftment, while enabling administration of gemtuzumab ozogamicin maintenance without prolonged haematologic toxicity. The findings suggest that gene edited donor grafts may provide a platform for post-transplant targeted therapies in patients at high risk of relapse after allogenic haematopoietic cell transplantation.
Reference
DiPersio JF et al. CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial. Nature Medicine. 2026; doi: 10.1038/s41591-026-04362-1.
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